1. Field of the Invention
The present invention relates generally to indolopyrrolocarbazoles and analogs thereof, more particularly to improved methods of making indolopyrrolocarbazoles and analogs thereof and their use as intermediates in the production of rebeccamycin and related analogs.
2. Description of the Background Art
Rebeccamycin and analogs thereof possess potent pharmaceuticaly activity especially the inhibition of tumor cell growth. For this reason, rebeccamycin and its analogs have been extensively studied for practical use as antitumor agents. The biologically active compounds are generally comprised of two components: an indolopyrrolocarbazole ring also referred to as rebeccamycin aglycone, and a sugar moiety which is covalently bonded to the ring. It is known that the biological activity of the compounds is closed associated with the rebeccamycin aglycone. Extensive research of the rebeccamycin aglycone has spurred a demand to find an efficient process of producing commercial quantities of the rebeccamycin aglycone and its analogs in a cost effective manner.
Several approaches to synthesizing rebeccamycin aglycone and its analogs have been reported in literature. See, for example, Gribble et al., Tetrahedron, 48, 8869 (1992), Moody et al., J. Org. Chem., 57, 2105 (1992), and Joyce et al., J. Org. Chem., 52 1177 (1987). It is known to react bisindolylmaleimides with oxidizing agents to synthesize the indolopyrrolocarbazole ring. Suitable oxidizing agents include dicyanodichloroquinone (DDQ), cupric chloride (CuCl2), cupric acetate (Cu(OAc)2), palladium chloride (PdCl2), palladium diacetate (Pd(OAc)2) and the like. The reaction rates and the availability of bisindolylmaleimides provide an efficient synthesis of the indolopyrrolocarbazole ring. However, these syntheses utilizing oxidizing agents have some limitations. For example, the use of DDQ as an oxidizing agent greatly complicates recovery of the desired product due to the products poor solubility. Iodine or cupric chloride used as oxidizing agents typically generate excessive by-products which significantly reduces overall yield and quality of the product.
It has been noted in the art that Pd(O2OCCF3) and palladium diacetate Pd(OAc)2 can suitably be used as oxidizing agents for synthesis of rebeccamycin aglycone. However, such oxidizing agents must often be used in excess to achieve acceptable oxidation levels. For example, palladium diacetate is capable of oxidizing bisindolylmaleimides to produce indolopyrrolocarbazole rings in acceptable yield levels, but at a level of 2.5 equivalents or 250 mol % of palladium diacetate. The need to use large amounts of the precious catalyst renders large-scale production of indolopyrrolocarbazole rings commercially impracticable.
Accordingly, there is a need for a method of making indolopyrrolocarbazoles rings such as indolo[2,3-a]pyrrolo[3,4-c]carbazoles in relatively high yields and with improved purity. It would be desirable to develop a process that is also low cost, and simple to perform. It would also be desirable to provide processes for making indolo[2,3-a]pyrrolo[3,4-c]carbazoles which may be used to provide a convenient source of intermediates for synthesizing biologically active compounds including rebeccamycin and analogs thereof.